Autoimmune diseases are often attributed to activation of self-reactive T cells specific for a restricted epitope on a self antigen. To date, treatments of autoimmune diseases have focused predominantly on nonspecific immunosuppressive approaches rather than focusing directly on the autoreactive T cell population. In these disease states, it would be useful to be able to induce T cell tolerance towards known antigens. T cells recognize peptide antigen bound in the groove of MHC molecules by means of the T cell receptor (TCR). Variable regions on both the a and b chains (Va and Vb) are involved in the binding of the MHC/peptide complex. However, there exists a class of antigens called superantigens (SAG) that binds a different region of MHC class II molecules and activates T cells based solely on the family of Vb that the TCR utilizes. Superantigens can be encoded endogenously by mouse mammary tumor viruses (mtv) in the mouse genome, or are synthesized exogenously by some bacteria and viruses. Encounter of these superantigens in the peripheral immune system leads to T cell activation first, followed by tolerance induction. We have initiated experiments to create a hybrid superantigen that maintains the tolerance-inducing activity of the superantigen yet can be directed towards T cells of any desired specificity. The initial construct was created by joining the nonpolymorphic region of the gene encoding the mtv 1 SAG to a nucleotide sequence encoding a peptide antigen, 91-104 of moth cytochrome C. This construct will be expressed in a baculovirus expression system, purified, then characterized for its ability to bind MHC molecules. The expressed molecule will be analyzed for its ability to induce tolerance in mice expressing a transgenic T cell receptor specific for the cytochrome C peptide. These experiments will be extended to a model autoimmune disease in which the construct will be altered to express the epitope of a self peptide involved in the disease. Thus, these studies will lead to the development of preclinical models for screening induction of tolerance to a desired antigen. 1. Vacchio MS, Ashwell JD. T cell tolerance. Chem Immunol 1994;58:1-33. 2. Kawano Y, Sasamoto Y, Vacchio MS, Hodes RJ, Gery I. Immune responses against self-TCR peptides. Cell Immunol 1994;159:235-45.